The identification of EGFR mutations in tumors of NSCLC patients has led to personalized molecular therapies and to a paradigm shift for patients with lung cancer candidates for targeted therapy. Furthermore, it has been established that EFGR mutations are key diagnostic biomarkers in NSCLC, therefore NSCLC patients genotyping for these alterations should be a standard of care right along standard clinical examination, pathology and imaging studies . Practice guidelines outlined by the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO) now include EGFR genotyping to guide therapy selection [44, 45].
Worldwide, 32.4% of NSCLCs involve EGFR mutations . Previous studies have established marked variations in EGFR rates depending on different geographic regions and race/ethnicity backgrounds. The frequency of mutations was greater for EGFR mutation-positive NSCLC patients of East Asian ethnicity than those of other ethnicities (30% versus 8%) . A slightly lower incidence of EGFR mutations (12%) has been identified among the Oceanic ethnicities and other insular Mediterranean patients with NSCLC [48, 49]. A prevalence of 21.2% of EGFR mutations has been observed in the ME and African NSCLC patients . Different frequencies of EGFR mutations have been found in Russia (18%), South Africa (23%), Australia (23.8%), and Latin America (26%) [50–53]. In our systematic review, an overall prevalence of 17.8% was identified in patients with EGFR mutation-positive NSCLC across the MENA region. The reported prevalence was slightly higher than those observed among Western populations but still lower than frequencies reported in Latino and Asian populations. In the Levant countries, a region flanked by the ME and Europe, and the Gulf region (also known as Arabian Gulf), the reported EGFR mutation frequency was 15.6%  and 28.7 , respectively. The lowest mutation frequencies were seen in Lebanon (8.8 to 12,7%) [31–33]. Among the Turkish population, an EGFR mutation frequency of 42.6% in NSCLC patients was identified in western Turkey , when Tezel et al., showed that the mutations rate in Turkish patients with EGFR mutation-positive NSCLC was 16.7% . Regional distribution of genetic mutations of lung cancer in Turkey, as reported in the (REDIGMA) study, including 25 centers, showed that mutation tests were found to be positive in 18.9% of these patients. The mutations were 69.9% EGFR, 26.3% ALK, 1.6%ROS and 2.2% PDL . Our systematic review also highlights a wide range in EGFR mutation frequencies in NA populations. The overall EGFR mutation rate of NSCLC patients varied from 15.9%  to 26.8%  in Morocco. Additionally, one Moroccan study showed similar EGFR incidence rates (21%) as in patients of Caucasian descent . An overall rate of 39.6% was found in EGFR mutation-positive NSCLC patients in Algeria . In Tunisia, while first reports account for an EGFR mutation frequency as low as 5.5% , other reports show discrepant data of 11.5% and 44% [40, 39].
The mechanism behind the differences of EGFR mutation rates across geographic regions and the race/ethnicity is still unclear. A persistent finding in the literature is the substantial variation in EGFR mutation prevalence across different geographic areas and among various race/ethnicity backgrounds . Although such mutations are over-represented in more than 40% of EGFR mutation-positive NSCLC in Japan and China, they are detected in roughly 15% of EGFR mutation-positive NSCLC patients in France and Italy . It has been demonstrated that ethnic genetic variation may explain these differences [55, 56]. In the ME, the frequency of EGFR mutations was reported to range between 16.6% and 44% in the Turkish population [22–26]. This disproportion is a result of the genetic heterogeneity and the ethnic diversity that characterize Turkey, a country endowed with a distinguished geographic location that is between Europe and Asia and near the ME. In NA, the EGFR mutation frequency in Tunisians range from 5.5% and 44% [38–40]. This disparity in frequencies is mainly attributable to the ethnicities that have succeeded in Tunisia, contributing to this country’s ethnic diversity and therefore genetic heterogeneity .
Some studies showed that difference in EGFR mutations frequencies might be caused by exposing to indoor and/or outdoor air pollution . The unique EGFR mutation spectrum in southwestern China might be related to the exposure of air pollution from local smoky coal and can reflect a specific environmental exposure .In Europe, a positive association between various indicators of indoor air pollution and lung cancer risk has also been reported . Indoor air pollution coal burning in poorly ventilated houses, burning of wood and other solid fuels, as well as fumes from high-temperature cooking using unrefined vegetable oils such as rapeseed oil . Cooking oil fumes from vegetable oils are mutagenic [62, 63]. The International Agency for Research on Cancer classifies outdoor air pollution as an established lung carcinogen in humans . In 2017, the global proportion of lung cancer deaths attributable to outdoor ambient PM2.55 air pollution was 14%, ranging from 4.7% in the United States to 20.5% in China . PM2.5 is generally described as fine particles and is emitted by vehicles, coal-burning in power plants, industrial activity, waste burning, and other human activities.
Several studies have reported a higher incidence of EGFR mutations among women in comparison to men, with figures up to 69.7%. In effect, up to 42% of females versus only 14% of males with NSCLC are expected to harbor an EGFR TK domain mutation [46, 47, 66]. In our review, EGFR mutation prevalence was higher in females (females versus males: 33.4% versus 17%).This is similar to data from Europe, Spain and other Asian studies which concluded that EGFR mutations were more common in women [67–69]. A systematic review covering 151 worldwide studies published in 2014 observed that the EGFR mutation-positive proportions were 60% and 37% in women and in men, respectively . Previous studies showed that women can be more exposed to domestic radon which poses a risk for lung cancer at exposure levels approaching those for underground miners . Others studies reported that domestic radon is associated with a low excess risk for lung cancer [71, 72]. Generally, women tend to be non-smokers or light smokers compared to men, but their domestic lifestyle may expose them to certain indoor mutagen. If the occurrence of EGFR mutations is associated with potential indoor mutagens, women would have a higher mutation rate than men . Furthermore, female endocrine factors such as progesterone receptor and aromatase expression could also play a role in the prevalence of the EGFR mutations . Further studies are needed to investigate the role of hormones in EGFR mutation-positive NSCLC.
In our review article, the prevalence of EGFR mutations was more than two folds higher in non-smokers than current smokers (31.1% versus 11.1%). In European or American studies, EGFR mutations rate in non-smokers ranged from 10–30% . EGFR mutations are the most common driver gene found in never-smoker adenocarcinoma from East Asia, constituting 60-78% of this subgroup [76–78]. While some studies found that non-smokers were associated with a significantly higher EGFR mutations prevalence . Others have reported an association between EGFR mutations and the amount and duration of cigarette smoking, with a higher incidence of mutations than that seen in never smokers . Furthermore, clinical studies have suggested that the pathogenesis, clinical manifestation, and prognosis of non-smokers and smokers are different in lung cancer tumors [81–83]. Genetic differences have been also found in the tumors of non-smokers versus smokers [84, 85]. The proportion of non-smokers with NSCLC is increasing. Multiple environmental factors are implicated in lung carcinogenesis including exposure to secondhand tobacco smoke, pre-existing lung diseases, and family history of cancer. Exposure to industrial substances such as toxin (ex: arsenic, nickel, chromium, tar, soot), some organic chemicals (ex: radon, asbestos), radiation exposure, air pollution, tuberculosis and environmental tobacco smoke in non-smokers also increases the risk of developing lung cancer. More thorough investigations are needed to pinpoint causal mutagens and determine the amplitude of their potential mutagenic capability.
Deletions in exon 19 and the single amino acid substitution L858R in exon 21 account for approximately 85%-90% of all EGFR mutations in NSCLC, they are the most common and can predict response to EGFR TKIs and confer sensitivity to EGFR TKIs . Exon 18 and 20 insertion mutations are less common and represent the remaining 10% of EGFR mutants in NSCLC. The exon 20 T790M point mutation, and most EGFR exon 20 mutations, are predictive of treatment resistance to first- and second-generation EGFR TKI therapies [44, 87]. In our article review, the average frequency of the exon 19 and substitutions in exon 21 were 45.2% and 30.9%, respectively, among all EGFR mutations. Together, these two mutations account for up to 76.1% of identified EGFR mutations. Our findings also identified potential EGFR TKI-resistant mutations in 11.2% (112/998) among which, the T790M substitution was the most prevalent resistance mutation to first-generation TKI (45.5%, 51/112). The low frequency of exon 19 del and the point mutation L858R at exon 21 (73.4%) among the MENA population is likely the result of the heterogeneity in screening and targeted methods, potentially engendering inaccuracies in the incidence rates of otherwise common EGFR mutations. Direct sequencing was the most commonly used methodology in MENA studies (45.9%, 11/24). However, Direct sequencing has some critical limitations among which the low mutation detection sensitivity; below a certain threshold of mutant DNA, mutations could not be detected. The sensitivity of this technique is under par in representative clinical tumor samples and can yield accurate results only at higher concentrations of mutant DNA . Soussa et al. showed that approximately 3% of NSCLC patients have rare mutations not identified by real-time PCR approaches . The molecular characterization of peripheral blood may provide a strategy for the non-invasive serial monitoring of tumor genotypes during treatment, particularly for the EGFR T790M mutation . The frequency of T790M mutation depends on the types of assays for this mutation . Oxnard et al. found that 31% of NSCLC patients who are negative for T790M on central tumor genotyping have detectable T790M in plasma and recommend that tissue biopsy T790M genotyping would be substituted by liquid biopsy . Other plasma assays have similarly identified unexpected false-positives for T790M in the absence of false-positives for other mutations . T790M mutational analysis in liquid biopsies is currently incorporated in recent guidelines for the management of acquired TKI resistance . Recent studies have confirmed that EGFR mutations from plasma can predict the clinical response to targeted therapy [95, 96]. In the MENA region, the T790M mutation, using liquid biopsy, has been conducted only in NSCLC patients from Lebanon . In addition, Next Generation Sequencing (NGS) has the ability to detect the whole exome or genome and is not restricted to specific target sequences. NGS can simultaneously analyze multiple variations, including uncommon alterations. Uncommon EGFR mutations make up a highly heterogeneous subgroup of NSCLCs that account for approximately 10%-18% of EGFR-mutated patients, and NGS testing can broaden the spectrum of alterations within the uncommon group in NSCLC patients . However, Non-invasive plasma-based detection of EGFR mutations using digital PCR is still the most suitable method in clinical EGFR testing, thanks to its higher sensitivity, easier-to-understand results, low turn-around time and low cost to predicting the efficiency of EGFR-TKI .
This report revealed that the molecular epidemiology of EGFR mutations is heavily influenced by ethnicity and geography; EGFR mutations were found to be more frequent in patients in the MENA region than in patients of caucasian ancestry, in contrast, the rates reported among Asian populations were quite higher. Although results from this study were consistent with findings in previous reports, they should be considered cautiously due to some limitations. Firstly, a considerable portion of the considered studies have low statistical power as 8 of them included less than 100 patients. This could misrepresent the true prevalence of EGFR mutations in the region. Also, data about the stage of the tumors lacked from the majority of the included studies. Therefore, the correlation of tumor-stage and EGFR mutational status remains undefined in the region. Furthermore, the majority of the analyzed cases of the studies had adenocarcinomas, consequently, the reported influence of this particular histological subtype on EGFR mutational status could be inaccurate. Despite these limitations, a major strength of this review is the inclusion of available studies from a wide range of countries in the region. These estimates can serve as a reference for future research or policy making. Since EGFR mutation rates vary depend depending on, inter alia, ethnicity, NSCLC patients genotyping should be a standard of care in the MENA region in order to have more accurate and realistic data on EGFR mutation frequencies.